Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma

Key Points Question Is fluoropyrimidine-based systemic chemotherapy effective in treating patients with inoperable low-grade mucinous appendiceal adenocarcinoma? Findings In this randomized crossover trial that included 24 patients, there was no significant difference in tumor growth between treatment and observation time periods. Meaning These findings suggest that patients with low-grade mucinous appendiceal adenocarcinoma did not derive clinically meaningful benefit from systemic fluoropyrimidine-based chemotherapy.

• The pattern of metastatic spread is also unique and is usually confined to the peritoneal cavity. Hematogenous spread to liver or lungs or lymph node metastasis is extremely unusual. The classification of PMP is controversial and multiple overlapping systems exist. 5 There are some series that make a distinction between disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA), both of which can present as pseudomyxoma peritonei. 6  cytoreduction score (CCS). 7 Post-surgical 5-year overall survival range from 52-75%, the 10-year survival rates are low in the range of 10-32% only. [9][10][11] Cytoreductive surgery followed by HIPEC is a protracted and strenuous procedure and results in significant morbidity and mortality. Therefore, only the best surgical candidates with little co-morbidity and an Eastern Cooperative  15 Given the insufficient prospective data regarding the use of chemotherapy and our clinical experience, we have opted to assess potential clinical benefit of systemic treatment. The current trial design will provided needed evidence regarding the impact of chemotherapy.
In particular the benefits of this study's trial design are: (1) randomization of patients will minimize the bias from patient selection and (2) a cross-over design will enable each patient to serve as their own control and allow intrapatient comparisons that will be better able to answer the question of whether chemotherapy is a benefit for appendix PMP. The purpose of this prospective study is to evaluate the impact of chemotherapy on a novel quantitative assessment of mucinous peritoneal disease form PMP.
Performing a randomized controlled trial will help in answering this question and will help us better understand the biology of this disease. This will also help guide future research/treatment efforts. Furthermore, the results of this trial may help us develop an alternative treatment strategy for patients with PMP who are not candidates for CRS. All surgically unresectable PMP/Well-differentiated mucinous appendiceal adenocarcinoma patients will be randomized to either Observation arm or Chemotherapy arm for 6 months and will then cross-over to the other arm at the end of this period ( Figure 2). Each person serves as their own control in the study. Randomization will be performed through CORE. The exact type of fluoropyrimidine-based chemotherapy is not mandated and final treatment decisions will be left to the medical oncologist who is administering the chemotherapy. All chemotherapy adjustments will be done by the treating medical oncologist according to standard of care practice.

Supportive Care
At all times patients will receive maximal supportive care treatments for cancerrelated symptoms. As bowel dysfunction is a common problem in this cancer these therapies may include the recommendations to eat multiple small meals a day or the use metoclopramide to help with gastrointestinal motility. If a bowel obstruction should occur than patients will be treated according to standard of care practice. Such treatment may include bowel rest, intravenous fluids, surgical consultation, venting G-tube, or total parental nutrition.
Protocol # 2012-1050 July 31, 2019 Page 16 of 27 4. Patients will be followed for overall survival/death once per year.

Evaluations During Study
5. All laboratory tests will be conducted as standard of care according to each treating physician and should generally include a complete blood count, electrolytes, and liver function tests (AST, ALT, Alkaline phosphatase, Total bilirubin). Tumor markers (CEA, CA19-9 and CA-125) will be done at baseline and elevated markers will be followed at each subsequent approximate 3 month visit.
6. Quality of life will be assessed using the generic QOL instrument, EORTC QLQ-C30 and the ovarian cancer specific subscale instrument, EORTC QLQ -OV 28, and the anxiety specific scale of Speilberger State/Trait Anxiety Inventory State (STAI) at baseline, and every 3 months (+/-2 weeks). The EORTC QLQ-C30 assesses the quality of life of cancer patients, the EORTC QLQ-OV28 assesses symptoms and side effects related to ovarian cancer, and the STAI assesses patients' anxiety. As question #58 on the EORTC QLQ-OV28 pertains only to female patients, male patients will be instructed not to answer this question and responses to this question will not be analyzed for male patients. The questionnaire will be given to the patient to complete at the visit and will be collected by the research staff in the clinic for each assessment. If the patient cannot complete the questionnaire before the end of the visit, they will be provided with a stamped, self-addressed envelope so that they can return the questionnaire by mail. 7. A CT scan (or MRI) of the abdomen and pelvis will be performed at baseline, and every 3 months (+/-2 weeks) as standard of care. Contrast enhanced imaging is strongly recommended. The modality and need for imaging of the chest will be determined by each treating physician. Standard RECIST evaluation will not be applicable due to disease characteristics. We will therefore use a modified peritoneal RECIST (mpRECIST) that has been utilized at MD Anderson to assess quantitative changes in mucinous peritoneal disease.

The Mishel Uncertainty in Illness Scale (MUIS) assesses patients'
perceptions of uncertainty about their symptoms, diagnoses, treatment, prognosis, and relationship with caregivers. It will be given at the start and end of the study. The questionnaire will be given to the patient to complete at the visit and will be collected by the research staff in the clinic for each assessment. If the patient cannot complete the questionnaire before the end of the visit, they will be provided with a stamped, self-addressed envelope so that they can return the questionnaire by mail.

Response Criteria
Quantitative changes in mucinous peritoneal disease will be measured using the modified peritoneal RECIST (response evaluation criteria in solid tumours). The general guidelines for tumor evaluation will follow the structure established by RECIST version 1.1 except for the two fundamental differences: (1) up to 5 lesions in the peritoneal cavity will be assessed and (2) mucinous lesions will be considered measurable disease. 17 Up to five areas of mucinous peritoneal involvement will be measured at each evaluation. These lesions will be termed the target lesions. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) Thickness at the level of S1 nerve root A sum of the longest diameters for all target lesions will be calculated and reported as the baseline sum diameters (LD). The baseline sum diameters will be used as reference by which to characterize the objective tumor measurement The standard RECIST criteria use changes in sum of 20% increase for progressive disease, and 30% shrinkage for a partial response, with stable disease occurring in between these two. However, as PMP is an indolent disease process these criteria will not be utilized in this study. In a pilot study of 10 patients the largest change in mpRECIST over a 6month period was 11%.
Thus, the use of mpRECIST sum will be used in a comparative manner between treatment and non-treatment arms.

Sample Size
Based on preliminary retrospective data collected from two readers calculating mpRECIST on 5 patients the mean change over a six month time period on various common colon cancer treatments is an increase of 1.6% and without treatment the increase is 9%. This provides a 7.4% effect size with standard error of 2.242%, so the 95% Confidence Interval (CI) is [2.95%, 11.74%]. The standard deviation of residuals is 3.47% for the random effects introduced by the two readers. If we consider both the variation introduced by different readers and variation of the treatment effects, the combined standard deviation of differences will be 4.135%. We have deemed a ≥5% difference in mpRECIST between observation and treatment periods (mpRECIST percent change on observation minus mpRECIST percent change on treatment) to represent a clinical meaningful difference between systemic chemotherapy treatment and observation. Thus, if we expect an 8% tumor difference between the two groups (Ha) and the sample size in each sequence group is 12 (a total sample size of 24), a 2 x 2 crossover design will 80% power to reject the null hypothesis that tumor shrinkage difference between control group and treatment group is less than or equal to 5% (Ho), assuming that the Crossover ANOVA square root of MSE is 4.0% (a rounded estimate from preliminary data) and using a crossover ANOVA with a 0.05 one-sided significance level.
As this is a cross-over design study over 12 months we anticipate that up to 20% of patients will not complete the full study period and thus plan to enroll up to 30 patients on this study to account for early drop-out or removal from the study. Patients who do not complete the entire 12 month study period will not be included in the primary efficacy analysis, but will be included in secondary analyses and adverse event analysis.

Efficacy Analysis
The primary objective is to determine if the difference in tumor growth rate for each patient, as measured by mpRECIST, between observation and systemic chemotherapy periods is ≥5%. The growth rate will be determined as the percent reduction from the start of the period to the 6 month measurement in that period. Crossover analyses will be performed according to Senn Descriptive statistics, such as mean, standard deviation and median will be used to summarize the function scale, symptom scale, and the global health status scale of QOL. Paired student's t-test will be carried out to assess the difference in QOL between baseline and 6 months and 6months and 12 months. For patients who couldn't complete a survey, every effort will be taken to record the reason. We will also compare the baseline patient characteristics, baseline QOL scores and change between baseline and 3 month, and 6 month and 9 month in QOL scores, between the patients who could versus who could not complete the 6 or 12 month evaluation. A multiple logistic regression model will be fit for the indicator of "missing 6-month data" or "missing 12-month data", using patients' baseline characteristics and previous (baseline and 3-month or 6 month and 9 month ) QOL scores as predictors. This model will help us to identify the factors that may have influenced patients' tendency of dropout. In addition to the primary analysis for the change of QOL between baseline and 6 month, and 6 month and 12 month, a linear mixed effect model will be fit for all patients to assess the change of QOL over time, where baseline QOL and time will be fitted as covariates (fixed effects) and patient effect will be included as a random effect. In order to avoid bias due to potential informative drop-outs (e.g., the patients with rapidly growing disease are more likely to drop out of the study), we will apply the pattern mixture model (PMM) (Little & Rubin, 1987) for Protocol # 2012-1050 July 31, 2019 Page 22 of 27 our data, which will include the patterns of missingness as a factor in the model. Sensitivity analysis could also be carried out to assess the robustness of our inference when different missing mechanisms are assumed, i.e., MAR (missing at random), MCAR (missing complete at random) and ID (informative dropouts).
For secondary analyses, semiquantitative response will be determined by the treating physicians, and for those with elevated tumor markers, the change in tumor markers will be determined with the 95% confidence intervals. The overall survival (OS) will be estimated using the Kaplan-Meier method for each study arm. The median OS will be calculated, along with the 95% confidence intervals.

Adverse Event Monitoring
The rate of adverse events will be monitored by a composite of death and bowel complications (defined as bowel perforation or hospitalization for bowel obstruction). This composite will be monitored in each arm. As bowel complications are reflective of the severity of progressive disease this monitoring will ensure that no unexpected differences in adverse events from progressive cancer are being observed between the two treatment arms.
During the study, adverse events will be continuously monitored according to the

Data and Protocol Management
Patients will be entered and randomized equally in Clinical Oncology Research System (CORE) and data will be collected in an excel database by the research team assigned to the study and all computer files will be password-protected and stored on institution computers behind the institution firewall to further ensure database security and all records are kept confidential. Patients will be seen by the research team at baseline and at each 3 month follow-up visit for the 12 month duration of the study. Following the completion of the 12 month study, patients will only be followed once per year for overall survival/death.
As this is a primarily an observational using known chemotherapy that has been extensively studied in colorectal cancer, chemotherapy related adverse events will not be captured. Only selected adverse events that will be monitored in our toxicity monitoring will be collected at each evaluation time-point and also patients will be instructed to contact the research nurse if any unplanned hospitalization occurs. From data collected at every 3 month (+/-2 week) evaluation and from data collected from unplanned hospitalizations the research team will follow toxicities relating to potential signs of peritoneal progression as discussed under the toxicity monitoring section.
Participant data will be kept confidential. When the questionnaire packets are given to patients, the patient's name will appear on a removable cover sheet, and a study identification number will be placed on each page of the questionnaire. Before the patient returns the questionnaire he/she will remove the cover sheet so no identifying information appears on the questionnaires. The patients' names will be linked to the study identification number in a database that will be password protected, with access restricted to the research coordinator and principal investigators.

Correlative Studies
All patients who sign consent for this study will provide consent for the collection of previously collected paraffin embedded tissue. Up to 30 unstained slides of 5 to 10 microns thick will be requested from the outside institution or prepared from the patient's tumor block, if applicable.
The large number of slides relates to the highly mucinous nature of this tumor type and low amount of actual tumor that will be present on each slide. The tissue will be stored at MD Anderson Cancer Center as per institutional Tissue Station requirements. Any residual tumor tissue above what is specified here will be returned to the sending institution. Collected paraffin embedded tissue will be handled by Surgical Oncology research personnel. Only the PIs and his authorized research staff will have access to the identifiable information from this study. All the samples extracted from the paraffin tissue used in this study will be coded and identifiers (name, medical record number) will not be present on any material that is undergoing analysis. Patient information and relevant data will be stored on passwordprotected institution computers behind the institution firewall. At the closure of this study all unused material will be either returned to the sending institution or destroyed.
The primary objective of the correlative studies is to identify the molecular abnormalities that occur in PMP. In particular we plan to identify common oncogenic DNA mutations in this cancer. As the technology for DNA sequencing is rapidly changing the exact platform used will depend on the most robust platform at the time of tumor tissue analysis.